Age-related hearing loss (presbyacusis) is among the most prevalent handicaps in humans over 65 years of age and will become an even greater health problem as population demographics shift towards the elderly. Studies of animal models of presbyacusis and of human temporal bones have provided a basic understanding of the histopathologic changes in the aging inner ear. However, knowledge about the primary cellular injury, the sequence of subsequent pathological events and the underlying molecular changes leading to loss of auditory function with age remains limited. This project proposes to address these issues through three specific areas of investigation. Aim 3.1 seeks to define the sequence of age-dependent histopathologic changes and to characterize age-related alterations in the expression of proteins in the gerbil cochlea. Aim 3.2 focuses on identifying and characterizing genes that show age-related alterations in their expression patterns in the gerbil inner ear. Aim 3.3 provides comparative data on human presbyacusis using similar approaches in studies of well-preserved, prospectively obtained human inner ears. The human studies will be driven by results obtained in Aims 3.1 and 3.2. The planned experiments will provide important new information concerning the cellular and molecular events leading to hearing loss in the elderly, and along with data obtained in Project 4, should form the rationale for designing pharmacological- gene-mediated therapies for the treatment and prevention of presbyacusis.